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Biomedical subjects

V Miller

Publications and source records attributed to V Miller.

At least 37 records · Page 2Linked to original sources
PubMed2001

Clinical outcome among HIV-infected patients starting saquinavir hard gel compared to ritonavir or indinavir.

OBJECTIVE: To compare the clinical response among patients who initiate protease inhibitor therapies with different virological potency. DESIGN: We analysed patients who started indinavir, ritonavir or saquinavir hard gel capsule (hgc) as part of at least triple therapy during prospective follow-up within the EuroSIDA study. METHODS: Changes in plasma viral load (pVL) and CD4 cell count from baseline were compared between treatment groups. Time to new AIDS-defining events and death were compared in Kaplan--Meier models, and Cox models were established to further assess differences in clinical progression (new AIDS/death). Adjustment was made for differences in baseline parameters, in particular pVL, CD4 cell count, and region of Europe. RESULTS: A total of 2708 patients (median follow-up: 30 months) were included, of which 556 started ritonavir (21%), 1342 indinavir (50%), and 810 saquinavir hgc (30%). The three groups were fairly evenly balanced at baseline regarding CD4 count, previous diagnosis of AIDS and pVL, After 12 months, the median changes in CD4 cell count were 90, 96 and 74 x 10(6) cells/l, respectively;P < 0.001, the proportions of patients with pVL < 500 copies/ml were 47, 54 and 41%; P < 0.001, and the proportions with clinical progression were 11.9, 9.2 and 11.9%, respectively; P = 0.20 (log-rank test). In multivariate models the relative risk of clinical progression for indinavir compared with saquinavir hgc was: 0.77 (0.60--0.99); P = 0.043, and for ritonavir 0.83 (0.62--1.11); P = 0.20. CONCLUSIONS: Saquinavir hgc was associated with an inferior long-term clinical response relative to indinavir, which was consistent with the observed differences in virological and immunological responses.

Administration, Oral↗
PubMed2001

International perspectives on antiretroviral resistance. Resistance to protease inhibitors.

The availability of protease inhibitors (PIs) and their combination with nucleoside reverse transcriptase inhibitors marked the passage of antiretroviral therapy (ART) from potential for control to effective suppression and thus substantially reduced rates of morbidity and mortality related to HIV. Even so, what was first hoped to be an immutable HIV DNA treatment target has proved to be prone to resistance mutations, with substitutions identified at more than 20 amino acid sites, which reduces PI susceptibility and increases resistance to treatment. The mutation patterns associated with each PI have been defined, and have been observed to occur at one of two locations: at or near the active site, or in the substrate cleavage site. The natural history of PI resistance has been extensively studied, and the genetic and cellular pathways are described in detail in this article. In addition, cross-resistance among PIs is now recognized to be fairly extensive, although the degree of cross-resistance varies with the number of mutations and the variants selected by drug pressure. Thus, it is still possible to salvage a response with another PI after a first regimen with another PI has failed. The extensive basic science and clinical experience with PIs in the fight against HIV are reviewed in this article, which provides data on resistance-mutation profiles, cellular resistance mechanisms, viral fitness studies, and clinical outcome trials with various first-line and subsequent regimens that contain PIs. It is hoped that the information provided will guide physicians in best using PIs as part of a logical and successful ART strategy.

Amino Acid Substitution↗
PubMed2001

The use of and response to second-line protease inhibitor regimens: results from the EuroSIDA study.

OBJECTIVE: To describe the use of second line protease-inhibitor (PI) regimens across Europe and to determine factors associated with virological and immunological response. DESIGN: Analysis of data from 984 patients with a median follow-up of 21 months enrolled in EuroSIDA. Patients started their second PI-containing regimen at least 16 weeks after starting the first PI-containing regimen and with viral load > 1000 copies/ml. METHODS: Virological response was defined as a viral load < 500 copies/ml and immunological response as an increase of 50 x 10(6)/l or more in CD4 lymphocyte count. RESULTS: The median CD4 cell count at starting the second PI was 171 x 10(6) cells/l; viral load was 4.45 log copies/ml. As a second PI regimen, 45% were using a dual PI, while of those on one PI, indinavir (42%) and nelfinavir (34%) were most common. In multivariate Cox models, a higher viral load at starting the second PI [relative hazard (RH), 0.67 per 1 log higher; 95% confidence interval (CI), 0.58-0.77; P < 0.0001) and a lower CD4 cell count (RH, 1.15 per 50% higher; 95% CI, 1.06-1.26; P = 0.0014) were associated with a reduced probability of virological response. Those who had achieved viral suppression on the first PI-regimen were more likely to respond to the second (RH, 1.65; 95% CI, 1.30-2.10; P < 0.0001) as were those who added one or two new nucleosides to their second PI. CONCLUSIONS: Patients who initiate a second PI regimen at lower viral load, higher CD4 cell count or who added new nucleosides tended to be more likely to achieve a viral load < 500 copies/ml. The roles of cross-resistance and adherence in response to second-line regimens needs further investigation.

Adolescent↗
PubMed2001

The virological response to highly active antiretroviral therapy over the first 24 weeks of therapy according to the pre-therapy viral load and the weeks 4-8 viral load.

OBJECTIVES: To describe the viral response to HAART by weeks 4 and 8 in previously antiretroviral-naive patients. To assess whether the weeks 4 or 8 viral loads are useful predictors of viral suppression by week 24. DESIGN: A large clinical database including 453 antiretroviral-naive patients whose plasma viral load was monitored every 4 weeks. METHODS: Observed probabilities of achieving a viral load < or = 500 copies/ml by week 24 (days 84-168) from starting highly active antiretroviral therapy (HAART) were calculated according to viral loads at weeks 4 and 8. RESULTS: A total of 42.4% of patients (153/361) reached < or = 500 copies/ml viral load by week 4 and 70.4% (245/348) by week 8. Viral suppression below 500 copies/ml by 4-8 weeks was similar irrespective of the pre-HAART viral load. In patients with viral loads above 10000 copies/ml at week 4, 60.6% (20/33) achieved < or = 500 copies/ml by week 24. In patients with viral loads still above 10000 copies/ml at week 8, only 42.3% (11/26) achieved < or = 500 copies/ml by week 24, and only 33.3% (3/9) maintained viral suppression below 500 copies/ml to week 48. CONCLUSION: Viral loads at weeks 4 and 8 should be monitored to detect early signs of low subsequent viral suppression. For previously antiretroviral-naive patients whose viral loads after 8 weeks of HAART are still above 10000, there is an urgent need to assess adherence to therapy, drug levels and resistance, so management can be modified accordingly to reduce the rate of week 24 virological failure.

Adult↗
PubMed2001

Challenging the platinum combinations: docetaxel (Taxotere) combined with gemcitabine or vinorelbine in non-small cell lung cancer.

The limited single-agent activity of cisplatin, its toxicity profile, and the inconvenience involved in hydrating patients has compelled researchers to investigate other treatments as possible alternative therapies in non-small cell lung cancer. More recently, interest has focused on the potential of nonplatinum combinations. Phase II studies show that the combination of docetaxel (Taxotere; Aventis, Antony, France) and gemcitabine is active in stage IIIB/IV non-small cell lung cancer not previously treated by chemotherapy. Response rates of up to 54% and a median survival time of 13 months have been reported. These data are comparable with the achievements of cisplatin-based combinations. A randomized phase II trial of docetaxel plus gemcitabine versus docetaxel plus cisplatin found that the two regimens were equally active in terms of response rate, median, and 1-year survival. However, the combination of docetaxel with gemcitabine produced significantly less neutropenia and nonhematologic toxicities. In combination, from 80% to 100% of the full single-agent gemcitabine and docetaxel doses can safely be administered once every 3 weeks. The combination of docetaxel plus vinorelbine is also active in non-small cell lung cancer and preliminary data suggest that this schedule with prophylactic filgrastim may optimize tolerability and dose intensity. In a phase II study using this approach, a confirmed response rate of 51% was obtained in 35 patients. At 12 months, the predicted median survival is 14 months and the predicted 1-year survival rate is 60%. Excessive lacrimation, fatigue, and onycholysis were cumulative toxicities. However, the incidence of mucositis and neuropathy was low with the combination of docetaxel and vinorelbine. Docetaxel combined with other new agents, particularly gemcitabine, may offer another useful alternative to cisplatin-based chemotherapy in patients with good performance status.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed2001

Structured treatment interruptions in antiretroviral management of HIV-1.

The consequences of treatment interruptions have been investigated in various patient populations. For patients with controlled viraemia, treatment interruption allowing viral rebound may boost HIV-1-specific immunity. The hypothesis that this will be sufficient to control HIV replication in the absence of treatment has received support in studies of patients initiating treatment during primary infections. In patients with chronic infection, treatment interruption has been shown to boost HIV-1-specific immunity in some cases. In patients with virological failure, despite drug-resistant virus, treatment appears to provide benefit, in that interruption results in a decrease in the CD4 cell count and increases in plasma HIV-1-RNA levels. The removal of drug pressure allows the rapid shift to wild-type virus. Whether this will be of benefit to the patient is not clear. Treatment interruption may help reduce the accumulation of long-term toxicities.

Anti-HIV Agents↗
PubMed2001

Quality of life in inflammatory bowel disease: a cross-cultural comparison of English and Canadian children.

BACKGROUND: Any disease and its treatment has an important impact on health-related quality of life for affected individuals. There have been few previous studies on the quality of life for children with inflammatory bowel disease (IBD). METHODS: A cross-cultural comparison was performed to determine whether the concerns of children with IBD in the United Kingdom are ranked similarly to those of children with IBD in Canada. An item reduction questionnaire, developed from interviews with Canadian children with IBD, was scored by 53 British children with IBD for importance and frequency, as a questionnaire had been scored previously by 117 Canadian children. RESULTS: There was a significant correlation between the mean scores (r = 0.831, P < 0.001) and ranks (r = 0.801, P < 0.001) for the 96 questions, and 43 of the 50 highest-ranking concerns corresponded for both populations. Confidence interval analysis showed a significant difference between the mean values for 21 of the 96 items; 20 of these 21 were ranked higher in the United Kingdom than they had been in Canada, suggesting that the frequency and/or degree of concern was greater for the British children with IBD. CONCLUSIONS: Health-related concerns of British children with Crohn disease and ulcerative colitis correlate closely with those of Canadian children with those diseases. Further studies are needed to determine the sensitivity of individual questions, the most appropriate wording of these questions, and the optimal length for a proposed instrument to assess quality of life in children with IBD.

Adolescent↗
PubMed2001

Laboratory guidelines for the practical use of HIV drug resistance tests in patient follow-up.

HIV drug resistance is one of the major limitations in the successful treatment of HIV-infected patients using currently available antiretroviral combination therapies. When appropriate, drug susceptibility profiles should be taken into consideration in the choice of a specific combination therapy. Guidelines recommending resistance testing in certain circumstances have been issued. Many clinicians have access to resistance testing and will increasingly use these results in their treatment decisions. In this document, we comment on the different methods available, and the relevant issues relating to the clinical application of these tests. Specifically, the following recommendations can be made: (i) genotypic and phenotypic HIV-1 drug resistance analyses can yield complementary information for the clinician. However, insufficient information currently exists as to which approach is preferable in any particular clinical setting; (ii) when HIV-1 drug resistance testing is required, it is recommended that testing be performed on plasma samples obtained before starting, stopping or changing therapy, on samples that have a viral load above the detection limit of the resistance test; (iii) the panel recommends that genotypic and phenotypic HIV-1 drug resistance testing for clinical purposes be performed in a certified laboratory under strict quality control and quality assurance standards; and (iv) the panel recommends that resistance testing laboratories provide clinicians with resistance reports that include a list of drug-related resistance mutations (genotype) and/or a list of drug-related fold resistance values (phenotype), with interpretations of each by an experienced virologist. The interpretation of genotypic and phenotypic analysis is a complex and developing science, and in order to understand HIV-1 drug resistance reports, communication between the requesting clinician and the expert that interpreted the resistance report is recommended.

Acquired Immunodeficiency Syndrome↗
PubMed2001

Mutational patterns in the HIV genome and cross-resistance following nucleoside and nucleotide analogue drug exposure.

A variety of key mutations in HIV reverse transcriptase (RT) have been associated with nucleoside reverse transcriptase inhibitor (NRTI) exposure, which give rise to a diverse range of effects in terms of altered drug susceptibilities, viral replicative capacity and RT biochemistry. There are three basic mechanisms of resistance conferred by specific mutations in the coding region of RT. The first is drug discrimination, whereby a particular drug or drugs are either selectively excluded from uptake or from the RT-primer-template catalytic complex. Drug discrimination is, for the most part, relatively specific for individual drugs. Repositioning of the template-primer to prevent a catalytically competent complex in the presence of a bound drug molecule has also been observed in some instances, and forms a second mechanism. The third, and potentially most significant for long-term efficacy of the NRTIs, is pyrophosphorolysis, the primary mode of resistance to zidovudine. Mutations selected by this drug or stavudine serve to elevate the natural rate of the reverse reaction for RT. Pyrophosphorolysis uncouples the last nucleoside monophosphate added to the proviral transcript, and attaches it to either a free pyrophosphate (regenerating a deoxynucleoside triphosphate) or to a nucleoside di- or triphosphate (usually ATP). Uncoupling a chain-terminating NRTI residue therefore rescues reverse transcription and reduces drug susceptibility across the class, since the process is not specific for the selecting drug. Of all the nucleoside-associated mutations, the best known and most studied are the six associated with thymidine analogue exposure. These six mutations (M41L, D67N, K70R, L210W, T215Y/F, K219Q) enhance RT pyrophosphorolysis to confer high-level viral resistance to zidovudine, and clinically significant loss of response to stavudine and didanosine. They have also been found to confer reduced susceptibility to lamivudine and abacavir, particularly when present alongside other NRTI-induced changes. Other key mutations generally confer more limited resistance to specific agents, although the primary lamivudine- and abacavir-associated M184V substitution generates a broad spectrum of drug-dependent phenotypes, and uncommon mutational complexes conferring resistance across the entire class are well known. In addition to 'classical' multi-nucleoside-resistant genotypes, database-driven 'virtual phenotyping' for accumulations of NRTI-associated mutations around a core of thymidine analogue-induced changes predicts drug susceptibilities below wild-type across the entire NRTI class, even in the absence of key mutations associated with individual agents. When the natural range of drug susceptibilities for treatment-naive isolates is used as the basis for defining resistance, retrospective analysis of clinical isolates in the Virco database shows a significantly increased incidence of reduced susceptibility for the dideoxy NRTIs (didanosine, stavudine and zalcitabine) that was undetected in previous assays. These data imply a cumulative degradation of response to

Anti-HIV Agents↗
PubMed2001

[Tamoxifen or tamoxifen in combination with chemotherapy in adjuvant therapy of breast carcinoma. Results of a multicenter randomized study].

UNLABELLED: Between April 1994 and May 1997 103 breast cancer patients (pts), pT1c-3a, pN0-1, M0, were randomised after surgery to adjuvant tamoxifen (20 mg per day) or to tamoxifen plus CMF (C 500 mg/m2, M 40 mg/m2 and F 600 mg/m2 on days 1st and 8th q 28 day) in 6 cycles. The median age (49-72 years, median 58), tumour size, number of involved lymphnodes (0-3), estrogens receptor status, grade (I-III) and type of operation were well balanced among the 50 pts on tamoxifen and the 53 pts on tamoxifen plus CMF pts, preferably postmenopausal. RESULTS: Grade of toxicity according to WHO criteria was not higher then two in both arms. Toxicity both haematological and non-haematological was higher in the group treated with chemotherapy (0 vs 32 resp. 20%) except weight gain (52% in both group). After median follow-up of 42 mos five recurrences in tamoxifen and seven in tamoxifen plus CMF pts were observed (p = NS). The projected 3-y DFS is 92% for tamoxifen and 88% for tamoxifen plus CMF (p = NS). The 3-y OS is 88% for tamoxifen and 80% for tamoxifen plus CMF pts (p = NS). CONCLUSIONS: Both regimens are equally effective with higher toxicity in the group with combined chemo- and hormonal therapy.

Aged↗
PubMed2000

Virological and immunological effects of treatment interruptions in HIV-1 infected patients with treatment failure.

OBJECTIVE: To analyse the immunological and virological effects of treatment interruptions in HIV-1-infected patients with treatment failure and multidrug-resistant virus. METHODS: Drug susceptibility was assessed using Antivirogram and genotypic analysis was based on population and clonal sequencing for 48 patients who had interrupted treatment (> or = 2 months). RESULTS: Treatment interruption resulted in viral load increases (mean 0.7 log 10 copies/ ml; P = 0.0001) and CD4 cell count decreases (mean 89 x 10(6) cells/l; P = 0.0001). A complete shift to wild-type virus at the phenotypic, genotypic and clonal level was observed in 28/45 patients. These patients differed from those that did not show a shift to wild type in baseline CD4 cell counts (192 versus 59 x 10(6) cells/l; P= 0.007) and in the relationship between baseline viral load and CD4 cell count (no correlation versus a significant negative correlation; P= 0.008). Response to re-initiation of treatment fell with increasing viral load [relative hazard (RH) 0.33; P= 0.001] and with increasing total number of drugs with reduced susceptibility (RH 0.51; P = 0.0003); it improved with the number of new drugs received (RH 2.12; P = 0.0002) and a shift to wild type (RH 5.22, P = 0.006). CONCLUSIONS: Changes in surrogate markers suggest that treatment provided benefit in spite of virological failure and resistant virus. Although patients with a shift to wildtype virus responded better in the short term to treatment re-initiation, the long-term effects are not known and the risk of immune deterioration needs to be carefully considered.

Adult↗
PubMed2000

Human motor development and hand laterality: a kinematic analysis of drawing movements.

This study examines the developmental profiles of basic 'open-loop' drawing movements on the non-dominant hand (ND) in comparison with the dominant hand (D). Fifty-three right-handed children aged 7-14 years and 15 adults aged 27-43 years were examined. Each subject drew lines and circles of different sizes at maximum velocity with a pressure-sensitive pen on a computer graphics tablet. Small lines were drawn at 90 degrees to the axis of the forearm (lines using wrist movements (LWM)) and along the axis of the forearm (lines using elbow movements (LEM)). Larger lines were drawn at 90 degrees to the axis of the forearm (LEM). At both extremities, the movement frequencies of the proximally generated drawing movements increased in a parallel fashion at different levels. In LWM, the right-left-differences (RLD) were high in 7- to 8-year-old children; until puberty, the ND hand reached almost the performance of the D hand. In contrast, the RLD of the LFM increased at the same time. As adulthood approaches, frequencies of all drawings increased further while the LWM on the ND side remained stable. In adults, there were similar RLD for all line drawings involving predominantly flexion and extension movements. When drawing circles, the RLD were highest, though stable in all age groups. Hand laterality of pen use changes over time; these changes are dependent on complexity (combined/sequential cf. flexion-extension muscle activation) and on topography (proximal cf. distal movements). Distinct developmental profiles of motoneuronal populations of the cortex may be responsible for the distinct hand laterality effects and the decreasing variability of motor patterns. The drawing abilities and developmental changes on the untrained ND hand indicate that effector-specific practice plays a minor role.

Adolescent↗
PubMed2000

The impact of protease inhibitor-containing highly active antiretroviral therapy on progression of HIV disease and its relationship to CD4 and viral load.

OBJECTIVE: To compare the rate of disease progression according to viral load and CD4 cell count in patients receiving or not receiving highly active antiretroviral therapy (HAART), defined as protease inhibitor-containing regimens. DESIGN: An observational study, with prospectively collected data. METHODS: All patients attending the HIV Outpatient clinic as of 1 January 1995 (n = 2083) were included. Follow-up was until the first AIDS-defining event or death. Associations between viral load or CD4 cell count and disease progression were assessed using a person-years approach. Event rates were compared using Poisson regression analysis; a multivariate model was used to assess the independent effects of CD4, viral load and treatment group on event rates and to consider interactions between these variables. RESULTS: The event rates increased with lower CD4 cell count and higher viral load for both treatment groups and were generally lower in the HAART group. In a multivariate analysis, lower CD4 cell counts and higher viral loads remained significantly associated with disease progression, irrespective of treatment group. However, the event rate was significantly lower for the HAART group compared with the control group (relative rate 0.53, P < 0.001). CONCLUSIONS: HAART-treated patients with high viral loads and CD4 cell counts experienced reduced disease progression compared with individuals with the same CD4 cell count and viral load not receiving HAART. Consequently, the short-term prognosis associated with viral load levels and CD4 cell counts may differ in patients on HAART. Whether this effect will be observed with non-protease-inhibitor-containing HAART is not known at this time.

Adolescent↗